Imagine this: A university researcher, believing she is hot on the trail of the genetic cause of bipolar affective disorder, logs onto a genome sequencing site and enters a search code. Immediately, a dialogue box appears on the screen with the message: "Please enter your credit card number and expiration date."
Science fiction? A bad dream? Or a vision of the next generation in genetic research? Probably none of these. But the time may well come when investigators will have to subscribe to a privately run service in order to test their data against the vast databases of human chromosome information.
Ownership of the human genome-or, more exactly, access to the tools and databases necessary to make sense out of the millions of bits of information that make up the estimated 100,000 human genes-constitutes one of the hottest scientific debates in the public policy arena. On one hand is the Human Genome Project (HGP), a worldwide consortium of governments and their supported researchers who are mapping the 23 pairs of human chromosomes and are determining the complete nucleotide sequence, involving 3 billion base pairs of DNA.
On the other, as many as 185 private labs financed by Wall Street and other financial centers are attempting to cover much of the same ground but are hoping to profit from the scientific community's need for the fundamental information. The debate encompasses not just science but sociology, politics, law and ethics.
The stakes are high. Human Genome Sciences Inc. (HGSI), a Maryland-based company, claims to have filed patents that "describe the medical uses of more than 5,500 newly discovered individual human genes." A study published in May by Decision Resources, a consulting firm, found "some 100 genome-based therapeutics-including recombinant proteins, gene therapies and antisense therapies-in development in the areas of cardiovascular disease, CNS disease, metabolic disorders, infectious disease, and cancer."
William A. Haseltine, Ph.D., chairman and CEO of HGSI, pinpointed the potential embodied in those patents in a statement issued last September. "HGSI's emerging patent portfolio has the potential to protect a wide variety of medical products of our own and our partners." He called the patents "a growing strategic asset." The statement went on to note that the company is filing its patents "to protect the commercial rights to gene-based medical inventions."
Reaction to the genome patents is mixed. The Council for Responsible Genetics (CRG) says, "Patents in science promote secrecy and hinder the exchange of information. By patenting products of research, the free flow of ideas and information necessary for cooperative scientific efforts is reduced."
The council adds, "Patents exploit taxpayer-funded research. The development of biotechnology rests on 50 years of federally funded biomedical research. Corporations can make profits on their patented products by charging high prices to the citizens whose tax dollars supported the research and development of the products. Citizens are unfairly being asked to pay twice for medicines and other products."
As a result, according to CRG's policy statement, "products such as drugs are often priced out of reach for many of those who need them."
"The intellectual property system in this country was developed on the premise that there needs to be intellectual property protection to incent industry to develop their products," says Kathy Hudson, Ph.D., assistant director for policy and public affairs of the National Human Genome Research Institute (NHGRI). "There is a point at which something is a clear innovation that warrants intellectual property protection. In genetics [by international agreement], the raw sequence data...fall below that line."
NHGRI, an agency of the National Institutes of Health, works with the Joint Genome Institute of the U.S. Department of Energy in coordinating the U.S. portion of the HGP, a 15-year program funded by the government and nonprofit foundations. They work closely with the Sanger Centre in the United Kingdom, which is funded by the Wellcome Trust, as well as with researchers in France, Germany, Japan and other countries, all of whom contribute their sequences to a publicly available Web site.
The goal of the HGP is to provide a complete record of the sequencing of DNA in the human genome. Originally, the program was expected to be completed by 2005, but last fall, as announcements of patent applications and commercial sequencing programs proliferated, the timetable was moved up. Researchers expect to have a "working draft" that will cover at least 90% of the human genome by March 2000 and a completed sequence in 2003.
The open Web site <www.ncbi.nlmnih.gov/genome/seq>, where data from researchers world-wide are posted as research is completed, is maintained by HGP. Scientists who need to test a particular sequence against a sample of their own may download the data from the site, and a map on the home page illustrates the progress day-by-day.
"Our sequencers deposit their data in the publicly accessible, free database within 24 hours of reaching a contiguous stretch of one-to-two kilobases," Hudson said. "There is new data being deposited every day."
In direct competition with the HGP is a company formed by a former government researcher, J. Craig Venter, Ph.D., which is planning to compile complete DNA sequences for three to five human subjects, along with a library of variations known as Single Nucleotide Polymorphisms (SNPs). SNPs are changes of a single base in the genetic sequence that is present in at least 1% of the population for a specific gene.
Venter's company, Celera Genomics, is attempting to complete its sequencing of the "consensus" genome by the end of 2001. The consensus genome "reflects the frequency of the variations, which in some cases are rare, and in some relatively frequent," according to Paul Gilman, Ph.D., director of policy planning at Celera. The data will be published on the Internet, but Celera plans to charge for the use of the data.
Celera has positioned itself as an information provider rather than a pure researcher, even though it is actively engaged in sequencing the genome itself. Its sequencing information will be posted in a publicly accessible database. Researchers and institutions will be charged a subscription fee that will enable them to make use of the data the company has compiled.
"As an analogy, we call people's attention to Lexis-Nexis, which provides subscribers with access to databases that comprise publicly available documents." Gilman said. "It's the way of searching and viewing those documents that makes it attractive to subscribe. Another analogy would be the Bloomberg model, which financial analysts use to understand corporate finance issues under some circumstances." (Lexis-Nexis is an online database company that provides legal research; Bloomberg Financial operates a proprietary news service for Wall Street-Ed.)
"We are different than other genomics companies in that our target audience is broad and deep," Gilman added. "Other companies have focused in on a few subscribers, typically the pharmaceutical companies. We hope to go much broader than that: pharmaceutical companies, biotechs, M.D.s, the average person on the street who wants to know something about their own genetic makeup.
"A consensus human genome is something we intend to make readily available for free," said Gilman. "The subscriber gets to have the tools, the other genomes that we are working on, the tools that allow you to compare genomes, the tools to search our database with sequences they may have. Will it be a secret? No. Will it be available in a more interesting form? Yes, for subscribers. The consensus sequence will be searchable with simple tools."
Hudson, however, remains skeptical. "If they succeed in making it publicly accessible, we will cheer that!" she said.
"You can't copyright data, but you can copyright a database," Gilman said. "In the U.S., you can't copyright the data in a database. That presents a problem for database companies and for groups like the American Chemical Association, which does the chemical abstracts, because there are pirates out there who distribute the data in competition with the originator. In Europe, it is a crime to pirate a database. Companies go to quite some expense to create them for someone else to copy them and profit from them. As we create tools, special algorithms for research, and software, we will, as any database company will, attempt to copyright those things."
Celera will seek patent protection on some portion of the genome, roughly between 100 and 300 genes. But Gilman said that was no more than an insurance policy. "That's aimed at doing something of what people do with databases in-house," he said.
"Patent the human genome? The exercise in making it public makes it not possible. But that's not the same as saying there shouldn't be patents on genes. It's understandable that companies making investments on specific genes should seek protection through patenting that gene," said Gilman.
Gilman says Celera does not see itself in competition with the government project. In fact, he says, the company has offered to collaborate with government researchers. "In October or November of last year, we worked with the [U.S. Department of Energy] DOE to come up with a memorandum of understanding that would allow us to share data on the three chromosomes that were assigned to the DOE under the public program," he said. "But the NIH asked the DOE not to sign. They said we should sign an agreement with them or with the Sanger Centre. But they never got back to us on it."
"Any decisions that any of the partners made," said Hudson, "we would like to see made by the international consortium." It seems unlikely that any agreement would be approved by the consortium that did not provide for complete public accessibility, as is required by the Bermuda Agreement, which in 1996 established the international consortium that is conducting the HGP.
Hudson also says that cooperation with Celera would be difficult because the two projects have different approaches to the research. HGP researchers have each taken specific chromosomes or defined segments of chromosomes. Celera uses what it calls a shotgun approach, which gathers data from a number of genome segments and assembles it based on overlapping sections.
"Technologically, there is no basis for collaboration," she said. "It's like you are mapping the U.S. The consortium says, 'I'll take California, Oregon and Washington, and you take the eastern seaboard.' But Celera is taking parts of Sacramento, Boston, Orlando and Richmond, and it won't know which it has until the end."
Hudson says that the greatest danger of allowing private companies to patent genome research will be increased costs for the public. "If the data were not publicly available and a private entity were to charge for access, it would be publicly funded researchers who would have to pay," she said. "There is a phenomenal amount of people doing searches every day. Our Web site gets between 3 million and 4.9 million hits from as many as 100,000 Web addresses a day, and there's a boatload of investigators at each site. If we were to charge to have access to genome data, think how much that would amount to."